H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use

ABSTRACT

The present invention describes novel nitrosated and/or nitrosylated H 2  receptor antagonist compounds, and novel compositions comprising at least one H 2  receptor antagonist compound that is optionally substituted with at least one NO and/or NO 2  group, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase. The present invention also describes methods for treating and/or preventing gastrointestinal disorders; improving gastroprotective properties of H 2  receptor antagonists; decreasing the recurrence of ulcers; facilitating ulcer healing; preventing and/or treating inflammations and microbial infections, ophthalmic diseases and disorders, multiple sclerosis, and viral infections; and decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/108,877 filed Nov. 17, 1998 and U.S. Provisional Application No.60/140,839 filed Jun. 28, 1999.

FIELD OF THE INVENTION

The present invention describes novel nitrosated and/or nitrosylated H₂receptor antagonist compounds, and novel compositions comprising atleast one H₂ receptor antagonist compound that is optionally substitutedwith at least one NO and/or NO₂ group, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, stimulatesendogenous synthesis of nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase. The present invention also provides methods for treatingand/or preventing gastrointestinal disorders; improving gastroprotectiveproperties of H₂ receptor antagonists; decreasing the recurrence ofulcers; facilitating ulcer healing; treating and/or preventinginflammations and microbial infections, ophthalmic diseases anddisorders, multiple sclerosis, and viral infections; and decreasing orreducing the gastrointestinal toxicity associated with the use ofnonsteroidal antiinflammatory compounds.

BACKGROUND OF THE INVENTION

H₂ receptor antagonists are a well known class of drugs used in themanagement of gastrointestinal disorders. H₂ antagonists competitivelyinhibit the interaction of histamine with H₂ receptors. Although H₂receptors are present in numerous tissues, including vascular andbronchial smooth muscle, they appear to have a minimal role inmodulating physiological functions other than gastric secretion.

H₂ receptor antagonists inhibit gastric acid secretion elicited byhistamine and other H₂ receptor agonists in a dose-dependent,competitive manner. The H₂ receptor antagonists also inhibit acidsecretion elicited by gastrin and, to a lesser extent, by muscarinicagonists. H₂ receptor antagonists inhibit basal (fasting) and nocturnalacid secretion and that stimulated by food, sham feeding, fundicdistention, and various pharmacological agents. The H₂ receptorantagonists reduce both the volume of gastric juice secreted and itshydrogen ion (H⁺) concentration. Despite their good antisecretoryproperties, H₂ receptor antagonists are not unanimously recognized asgastroprotective agents. In addition, there is a high relapse rateassociated with treating gastrointestinal disorders with H₂ receptorantagonists as they do not eliminate Helicobacter pylori (Campylobacterpylori), the bacteria responsible for peptic ulcer disease, gastriclymphoma and adenocarcinoma.

A variety of adverse reactions have been ascribed to H₂ receptorantagonists, such as cimetidine and ranitidine, reflecting, in part, thevery large number of patients who have been treated with these drugs.The incidence of adverse reactions is low, and the adverse reactions aregenerally minor. The low incidence is attributable in part to thelimited function of H₂ receptors in organs other than the stomach and tothe poor penetration of these agents across the blood-brain barrier.

The most common side effects of H₂ receptor antagonists, such ascimetidine, are headache, dizziness, nausea, myalgia, skin rashes, anditching. The incidence of symptoms related to the central nervous system(CNS) appears to be higher in the elderly and in patients with impairedrenal function. Loss of libido, impotence and gynecomastia are sometimesobserved in patients who receive long-term therapy with high doses of H₂receptor antagonists, such as cimetidine.

Sorba et al, Arzneim-Forsch Drug Res., 47(II):849-854 (1997), thedisclosure of which is incorporated by reference herein in its entirety,have developed a drug that combines a H₂ receptor antagonist with anitric oxide (NO)-donor furoxan moiety. This drug is reported to retainweaker H₂ receptor antagonist activity relative to the parent drug butshows a NO-dependent gastroprotective effect.

U.S. Pat. No. 5,403,830, the disclosure of which is incorporated byreference herein in its entirety, describes pharmaceutical compositionsand methods of treating gastrointestinal disorders by administeringbismuth-containing agents in conjunction with a H₂ receptor antagonist.U.S. Pat. Nos. 5,403,830, and 5,407,688, and Ivnov et al, J. Pharm.Pharmacol., 48:297-301 (1996) and Marazova et al, J. Pharm. Pharmacol.,49:791-795 (1997), the disclosures of each of which are incorporated byreference herein in their entirety, describe treating or preventinggastrointestinal disorders by administering bismuth containing agents.U.S. Pat. Nos. 4,705,683, 4,900,741, 5,112,850 and 5,656,652, thedisclosures of which are incorporated by reference herein in theirentirety, describe administering H₂ receptor antagonists withpolyacrylates, antimuscarinic agents, trapencine and antacids,respectively. U.S. Pat. No. 5,656,652, the disclosure of which isincorporated by reference herein in its entirety, describes the use ofH₂ antagonists and antacids for the treatment of gastrointestinaldisorders.

The administration of NSAIDs, such as indomethacin or ibuprofen, with H₂receptor antagonists, such as cimetidine, is described in U.S. Pat. Nos.5,037,815 and 4,279,906 and in WO 94/07541, the disclosure of each ofwhich is incorporated by reference herein in its entirety. U.S. Pat.Nos. 5,102,902, 5,541,212 and 5,578,597, the disclosures of each ofwhich are incorporated by reference herein in their entirety, disclosethe use of H₂ receptor antagonists for treating multiple sclerosis andretrovirus infections.

There is a need in the art for H₂ receptor antagonist compounds thathave gastroprotective properties, decrease the recurrence of ulcers,facilitate ulcer healing and that can be used at low dosages. Thepresent invention is directed to these, as well as other, importantends.

SUMMARY OF THE INVENTION

The present invention provides compounds comprising a H₂ receptorantagonist to which is linked at least one NO and/or NO₂ group (i.e.,nitrosylated and/or nitrosated). The H₂ receptor antagonists can be, forexample, histamine analogs that contain a bulky side chain instead of anethylamine moiety and retain the imidazole ring of histidine, such ascimetidine. The imidazole ring can be replaced by a furan (e.g.,rantidine) or a thiazole (e.g., famotidine, nizatidine). The H₂ receptorantagonists can also be, for example, amide derivatives, such as, forexample, roxatidine or a guanidino derivative, such as, for example,ebrotidine or famotidine. The present invention also providescompositions comprising such compounds in a pharmaceutically acceptablecarrier.

Another aspect of the invention provides compositions comprising atleast one H₂ receptor antagonist, that is optionally substituted with atleast one NO and/or NO₂ group (i.e., nitrosylated and/or nitrosated),and at least one compound that donates, transfers or releases nitricoxide and/or stimulates endogenous production of nitric oxide (NO) orendothelium-derived relaxing factor (EDRF) in vivo and/or is a substratefor nitric oxide synthase.

Yet another aspect of the present invention provides methods fortreating gastrointestinal disorders, improving the gastroprotectiveproperties of H₂ receptor antagonists, increasing the rate of ulcerhealing, decreasing the rate of recurrence of ulcers, treatinginflammations, treating ophthalmic diseases and disorders, and treatingmicrobial infections in a patient in need thereof which comprisesadministering to the patient at least one H₂ receptor antagonistcompound, that is optionally substituted with at least one NO and/or NO₂group (i.e., nitrosylated and/or nitrosated), and, optionally, at leastone compound that donates, transfers or releases nitric oxide and/orstimulates endogenous production of NO or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The H₂ receptor antagonist that isoptionally linked to at least one NO and/or NO₂ group and nitric oxidedonor can be administered separately or as components of the samecomposition.

The present inventions also describes methods to decrease or reversegastrointestinal toxicity and facilitate ulcer healing resulting fromthe administration of nonsteroidal antiinflammatory drugs (NSAIDs);methods to improve the gastroprotective properties, anti-Helicobacterproperties and antacid properties of H₂ receptor antagonists; methodsfor preventing or treating gastrointestinal disorders; methods fortreating multiple sclerosis; methods for treating ophthalmic diseasesand disorders; and methods for treating viral infections, such as HIVdisease. The nitrosated and/or nitrosylated NSAID and nitric oxide donorcan be administered separately or as components of the same composition.These and other aspects of the present invention are explained in detailherein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is the synthetic scheme for the preparation of nitrite-containingguanidino derivatives of the compound of formula (I).

FIG. 2 is the synthetic scheme for the preparation of anitrosothiol-containing guanidino derivatives of the compound of formula(II).

FIG. 3 is the synthetic scheme for the preparation of nitritederivatives of the compound of formula (II).

FIG. 4 is the synthetic scheme for the preparation of nitrosothiolderivatives of the compound of formula (II).

FIG. 5 is the synthetic scheme for the preparation of nitrite-containingguanidino derivatives of the compound of formula (III).

FIG. 6 is the synthetic scheme for the preparation ofnitrosothiol-containing guanidino derivatives of the compound of formula(III).

FIG. 7 shows the gastric lesion scores of (a) vehicle alone (open bar,n=14); (b) cimetidine in vehicle (stipped bar); and (c) example 1(nitrosylated cimetidine) in vehicle (checked bar). Cimetidine at 160μmol/kg (n=6) and 320 μmol/kg (n=16) did not significantly inhibit theformation of gastric lesions relative to vehicle alone. Example 1(nitrosylated cimetidine) at 160 μmol/kg (n=9) and 320 μmol/kg (n=18)inhibited the formation of gastric lesions relative to vehicle alone(p<0.05). At the higher concentration, the gastric lesion score ofexample 1 and cimetidine were significantly different (p<0.05).

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“Gastrointestinal disorder” refers to any disease or disorder of theupper gastrointestinal tract of a patient including, for example, pepticulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel(anastomosis) syndrome, hypersecretory states associated with systemicmastocytosis or basophilic leukemia and hyperhistaminemia, and bleedingpeptic ulcers that result, for example, from neurosurgery, head injury,severe body trauma or burns.

“Upper gastrointestinal tract” refers to the esophagus, the stomach, theduodenum and the jejunum.

“Ulcers” refers to lesions of the upper gastrointestinal tract liningthat are characterized by loss of tissue. Such ulcers include gastriculcers, duodenal ulcers and gastritis.

“H₂ receptor antagonist” refers to any compound that reversibly orirreversibly blocks the activation of any H₂ receptor.

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Patient” refers to animals, preferably mammals, more preferably humans.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Nitric oxide adduct” or “NO adduct” refers to compounds and functionalgroups which, under physiological conditions, can donate, release and/ordirectly or indirectly transfer any of the three redox forms of nitrogenmonoxide (NO⁺, NO⁻, NO.), such that the biological activity of thenitrogen monoxide species is expressed at the intended site of action.

“Nitric oxide releasing” or “nitric oxide donating” refers to methods ofdonating, releasing and/or directly or indirectly transferring any ofthe three redox forms of nitrogen monoxide (NO⁺, NO⁻, NO.), such thatthe biological activity of the nitrogen monoxide species is expressed atthe intended site of action.

“Nitric oxide donor” or “NO donor” refers to compounds that donate,release and/or directly or indirectly transfer a nitrogen monoxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

“Alkyl” refers to a lower alkyl group, a haloalkyl group, an alkenylgroup, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl groupor a heterocyclic ring, as defined herein.

“Lower alkyl” refers to branched or straight chain acyclic alkyl groupcomprising one to about ten carbon atoms (preferably one to about eightcarbon atoms, more preferably one to about six carbon atoms). Exemplarylower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl,and the like.

“Haloalkyl” refers to a lower alkyl group, an alkenyl group, an alkynylgroup, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclicring, as defined herein, to which is appended one or more halogens, asdefined herein. Exemplary haloalkyl groups include trifluoromethyl,chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to a branched or straight chain C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon double bonds. Exemplaryalkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl,2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl,octen-1-yl, and the like.

“Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

“Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl,8-azabicyclo[3,2,1]oct-2-enyl and the like.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarboncomprising from about 3 to about 8 carbon atoms. Cycloalkyl groups canbe unsubstituted or substituted with one, two or three substituentsindependently selected from alkyl, alkoxy, amino, alkylamino,dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl,ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cyclohepta,1,3-dienyl, and the like.

“Heterocyclic ring or group” refers to a saturated or unsaturated cyclichydrocarbon group having about 2 to about 10 carbon atoms (preferablyabout 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms arereplaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. The heterocyclicring or group can be fused to an aromatic hydrocarbon group.Heterocyclic groups can be unsubstituted or substituted with one, two orthree substituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylicacid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylicester, amidyl, ester, carboxamido, alkylcarboxamido, arylcarboxamido,sulfonic acid, sulfonic ester, sulfonamido and nitro. Exemplaryheterocyclic groups include pyrrolyl,3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl,pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl,2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl,2-imidazonlinyl, imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl,1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl,quinolinyl, and the like.

“Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

“Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclicring system comprising one or two aromatic rings. Exemplary aryl groupsinclude phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl,indanyl, indenyl, indoyl, and the like. Aryl groups (including bicylicaryl groups) can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid,alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester,alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido,alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamidoand nitro. Exemplary substituted aryl groups include tetrafluorophenyl,pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and thelike.

“Alkylaryl” refers to an alkyl group, as defined herein, to which isappended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

“Arylalkyl” refers to an aryl radical, as defined herein, attached to analkyl radical, as defined herein.

“Cycloalkylalkyl” refers to a cycloalkyl radical, as defined herein,attached to an alkyl radical, as defined herein.

“Heterocyclicalkyl” refers to a heterocyclic ring radical, as definedherein, attached to an alkyl radical, as defined herein.

“Arylheterocyclic ring” refers to a bi- or tricyclic ring comprised ofan aryl ring, as defined herein, appended via two adjacent carbon atomsof the aryl ring to a heterocyclic ring, as defined herein. Exemplaryarylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

“Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy,cyclopentyloxy, and the like.

“Arylalkoxy or alkoxyaryl” refers to an alkoxy group, as defined herein,to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

“Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended toan alkyl group, as defined herein. Exemplary alkoxyalkyl groups includemethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

“Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appendedto a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkylgroups include 4-methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

“Haloalkoxy” refers to a haloalkyl group, as defined herein, to which isappended an alkoxy group, as defined herein. Exemplary haloalkyl groupsinclude 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

“Hydroxy” refers to —OH.

“Oxo ” refers to ═O.

“Oxy ” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganic cation.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted ammonium cations, and thelike.

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations such as for example,sodium, potassium, and the like.

“Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended toan alkyl group, as defined herein.

“Amino” refers to —NH₂.

“Nitrate” refers to —O—NO₂.

“Nitrite” refers to —O—NO.

“Thionitrate” refers to —S—NO₂.

“Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO₂ and “nitrosated” refers to compoundsthat have been substituted therewith.

“Nitroso” refers to the group —NO and “nitrosylated” refers to compoundsthat have been substituted therewith.

“Nitrile” and “cyano” refer to —CN.

“Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (Cl),and/or fluorine (F).

“Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkylamino groups include methylamino, ethylamino,butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, as definedherein.

“Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

“Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

“Alkylarylamino” refers to R₅₂R₅₅N—, wherein R₅₂ is an alkyl group, asdefined herein, and R₅₅ is an aryl group, as defined herein.

“Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein.

“Aminoaryl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an aryl group, as defined herein.

“Thio” refers to —S—.

“Sulfinyl” refers to —S(O)—.

“Methanthial” refers to —C(S)—.

“Thial” refers to ═S.

“Sulfonyl” refers to —S(O)₂.

“Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation.

“Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonic acid” refers to an sulfonic acid group, as defined herein,appended to an aryl group, as defined herein

“Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkyl group, anaryl group, an alkylaryl group or an aryl heterocyclic ring, as definedherein.

“Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein, and R₅₁and R₅₇ when taken together are a heterocyclic ring, a cycloalkyl groupor a bridged cycloalkyl group, as defined herein.

“Alkylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an aryl group, as defined herein.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein.

“Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, as definedherein.

“Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkyl group, asdefined herein.

“Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an aryl group, asdefined herein.

“Amidyl” refers to R₅₂₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein.

“Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, an alkylgroup, an aryl group, an alkylaryl group, or an arylheterocyclic ring,as defined herein.

“Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group or an arylheterocyclic ring, as defined herein, or R₅₁and R₅₇ taken together are a heterocyclic ring, a cycloalkyl group or abridged cycloalkyl group, as defined herein.

“Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, an organiccation or an inorganic cation, as defined herein.

“Carbonyl” refers to —C(O)—.

“Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkyl group, asdefined herein.

“Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkyl group,an aryl group, an alkylaryl group or an aryl heterocyclic ring, asdefined herein.

“Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, asdefined herein, appended to a carboxyl group, as defined herein.

“Alkylcarboxylic ester” refers to an alkyl group, as defined herein,appended to a carboxylic ester group, as defined herein.

“Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

“Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, asdefined herein, appended to a carboxylic ester group, as defined herein.

“Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group or an arylheterocyclic ring, as defined herein, and R₅₁and R₅₇ when taken together are a heterocyclic ring, a cycloalkyl groupor a bridged cycloalkyl group, as defined herein.

“Alkylcarboxamido” refers to an alkyl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Arylcarboxamido” refers to an aryl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Urea” refers to —N(R₅₈)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, and R₅₈ areeach independently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein, or R₅₁and R₅₇ taken together are a heterocyclic ring, a cycloalkyl group or abridged cycloalkyl group, as defined herein.

Compounds that donate, transfer or release nitric oxide species in vivohave been recognized as having a wide spectrum of advantages andapplications. The present invention is based on the unexpected discoveryof the effects of such compounds alone and together with one or more H₂receptor antagonists and/or one or more H₂ receptor antagonists directlyor indirectly linked with one or more nitric oxide moieties. Treatmentor prevention of gastrointestinal disorders, improved gastroprotectiveproperties, decreased rate of recurrence of ulcers (preferably pepticulcers), faster ulcer healing, treatment of inflammations, treatment ofophthalmic diseases and disorders and treatment of microbial infectionscan be obtained by the use of the nitrosated and/or nitrosylated H₂receptor antagonists of the present invention; or by the use of thenitrosated and/or nitrosylated H₂ receptor antagonists in conjunctionwith one or more compounds that donate, release or transfer nitric oxideand/or stimulate endogenous production of NO and/or EDRF in vivo and/oris a substrate for nitric oxide synthase.

The present invention is also based on the discovery that it is possibleto administer at least one H₂ receptor antagonist, optionally linked toat least one NO and/or NO₂ group, and at least one nitric oxide donor totreat gastrointestinal disorders, improve gastroprotective properties,decrease the rate of recurrence of peptic ulcers and increase the rateof ulcer healing of H₂ receptor antagonists, to treat inflammations andmicrobial infections, and to treat ophthalmic diseases and disorders. H₂receptor antagonists are compounds that competitively inhibit theinteraction of histamine with H₂ receptors. A nitric oxide donor is acompound that contains a nitric oxide moiety and releases or chemicallytransfers nitric oxide to another molecule, as defined herein.

The compounds and compositions of the present invention are novel andcan be used to treat numerous gastrointestinal disorders, inflammations,microbial infections and ophthalmic diseases and disorders. Suchgastrointestinal disorders include, for example, peptic ulcers, stressulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel(anastomosis) syndrome, hypersecretory states associated with systemicmastocytosis or basophilic leukemia and hyperhistaminemia, and bleedingpeptic ulcers that result, for example, from neurosurgery, head injury,severe body trauma or burns. Such inflammations and/or microbialinfections include, for example, inflammations and/or infections of theeyes, ears, nose, and/or skin. Such ophthalmic diseases and disordersinclude, for example, glaucoma, inflammation of the eye, and elevationof intraocular pressure. The compounds and compositions of the presentinvention can also be used as a pre-anesthetic medication in emergencyoperations to reduce the danger of aspiration of acidic gastric contents

The H₂ receptor antagonist compounds that are nitrosated and/ornitrosylated in accordance with the invention and/or are included in thecompositions of the invention can be any of those known in the art,including those exemplified below.

Cimetidine (marketed under the trade name TAGAMET® by SmithKline BeechamPharmaceuticals, Philadelphia, Pa.) is one of the most widely usedanti-secretory agents in the treatment of gastric ulcers. This compoundblocks the histamine receptors within the stomach mucosa, therebypreventing histamine molecules from signalling the stomach cells tosecrete acid. H₂ receptor blocking agents that are more potent thancimetidine (e.g. ranitidine, nizatidine) are also widely used. Althoughthe H₂ receptor blocking anti-secretory agents are effective in treatinggastrointestinal disorders, they do not have any gastroprotectiveproperties and, in addition, there is a high recurrence of ulcersassociated with their use.

Another group of H₂ receptor antagonists are amide derivatives, whichinclude, for example, roxatidine.

Yet another group of H₂ receptor antagonists are guanidino derivatives,which include, for example, famotidine and ebrotidine.

Other H₂ receptor antagonists contemplated by the present inventioninclude burimamide, metiamide, tiotidine and oxmetidine.

Each of the above contemplated H₂ receptor antagonists is described morefully in the literature, such as in Goodman and Gilman, ThePharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995,Pgs. 901-915; the Merck Index on CD-ROM, Twelfth Edition, Version 12:1,1996.

In one embodiment, the present invention describes nitrosated and/ornitrosylated compounds of Formula (I):

wherein

A is CH, nitrogen or sulfur;

B is oxygen, S(O)_(o) or CH₂;

o is an integer from 0 to 2;

D₁ is a hydrogen atom or D;

R₁ is a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, ahydroxyalkyl group, an alkoxyalkyl group or an aminoalkyl group;

R₂ is a lone pair of electrons, a nitrile group, a nitro group, analkylsulfonyl group, an arylsulfonyl group, an alkylcarbonyl group, acarboxamido group, a carboxylic ester or a cycloalkylalkyl group;

R₃ is:

with the proviso that at least one D₁ must be D if there is no Ddesignated in the structure;

R₆ and R₇ are each independently K, a hydrogen atom, a lower alkylgroup, an alkylaryl group, an arylcarbonyl group, an alkylcarbonylgroup, or R₆ and R₇ taken together with the nitrogen atom to which theyare attached are a heterocyclic ring;

R₈ and R₉ are independently a hydrogen atom or a lower alkyl group;

D is Q or K; with the proviso that D is hydrogen or K for the compoundsof formula (I)_;

Q is —NO or —NO₂;

K is—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(l)—W_(g)—(C(R_(e))(R_(f)))_(z)—T—Q;

a, b, c, d, g, i and j are each independently an integer from 0 to 3;

p, x, y and z are each independently an integer from 0 to 10;

W at each occurrence is independently —C(O)—, —C(S)—, —T—,—(C(R_(e))(R_(f)))_(h)—, an alkyl group, an aryl group, a heterocyclicring, an arylheterocyclic ring, or —(CH₂CH₂O)_(q)—;

E at each occurrence is independently —T—, an alkyl group, an arylgroup, —(C(R_(e))(R_(f)))_(h)—, heterocyclic ring, an arylheterocyclicring, or —(CH₂CH₂O)_(q)—;

h is an integer form 1 to 10;

q is an integer of from 1 to 5;

R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, aheterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, adialkylamino, an arylamino, a diarylamino, an alkylarylamino, analkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid,an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano,an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, analkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, anamidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, acarboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, ahaloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, asulfonic ester, a carbamoyl, a urea, a nitro, —T—Q, or(C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f) taken together with thecarbon atoms to which they are attached are a carbonyl, a methanthial, aheterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;

k is an integer from 1 to 3;

T at each occurrence is independently a covalent bond, a carbonyl, anoxygen, —S(O)_(o)— or —N(R_(a))R_(t)—;

o is an integer from 0 to 2;

R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;

R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, analkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, analkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, acarboxamido, a carboxylic ester, an amino alkyl, an amino aryl,—CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M³⁰ , wherein M⁺ is an organicor inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂)⁻.M⁺, or R_(e) or R_(f) are T—Q or(C(R_(e))(R_(f)))_(k)—T—Q, then the “—T—Q” subgroup designated in X canbe a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, ahydroxy, a heterocyclic ring or an aryl group.

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(j) can be a substituenton any disubstituted nitrogen contained within the radical where R_(i)is as defined herein.

In cases where multiple designations of variables which reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E—E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

Another embodiment of the present invention describes nitrosated and/ornitrosylated compounds of the Formula (II):

wherein

R₅ is a hydrogen atom, a hydroxy group or a hydroxyalkyl group; and

q, B and D are as defined herein.

Another embodiment of the present invention describes nitrosated and/ornitrosylated compounds of Formula (III):

wherein

D₂ is D₁ or a lone pair of electrons;

R₄ is:

B, D and D₁ are as defined herein, with the proviso that at least one D₁must be D, and D is as defined herein.

Compounds of the present invention that have one or more asymmetriccarbon atoms may exist as the optically pure enantiomers, purediastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The present invention includes within itsscope all such isomers and mixtures thereof.

The present invention includes within its scope compounds which mayexist in more than one resonance form and the effect that may have onthe positions at D₁ substituents designated in the above structures. Theinvention also includes within its scope the regiomers of the doublebonds of the substituted guanidino or amidino groups.

Another aspect of the present invention provides processes for makingthe novel compounds of the invention and to the intermediates useful insuch processes. The compounds of Formulas (I), (II) and (III) can besynthesized by one skilled in the art following the methods and examplesdescribed herein. For example, the compounds of the invention can besynthesized as shown in FIGS. 1-6, in which A, B, D, D₁, E, K, Q, T, W,R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R_(e), R_(f), a, b, c, d, g, i, j,p, q, x, y and z are as defined herein or as depicted in the reactionschemes for Formulas (I)-(III); P¹ is an oxygen protecting group; and P²is a sulfur protecting group. The reactions are performed in solventsappropriate to the reagents and materials used are suitable for thetransformations being effected. It is understood by one skilled in theart of organic synthesis that the functionality present in the moleculemust be consistent with the chemical transformation proposed. This will,on occasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol-groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, John Wiley & Sons, New York (1991).

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by oneskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Nitroso compounds of formula (I), wherein R₁, R₂, R₃, R₆, R₇, R₈ and R₉,are as defined herein, and a nitrite containing acyl group isrepresentative of the D₁ group as defined herein can be prepared asoutlined in FIG. 1. The synthesis of acylated prodrugs of substitutedguanidines is well known in the art. EP 743320 and WO 97/33576, thedisclosures of each of which are incorporated by reference herein intheir entirety, describe the preparation of acylguanidine andacylamidine derivatives as thrombin inhibitor prodrugs. The guanidinoderivative of structure 1 is converted to the acylated guanidinoderivative of structure 2 wherein R is—W_(a-1)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—T—Qby reaction with an appropriate protected alcohol containing acidwherein P¹ is as defined herein. Preferred methods for the preparationof acylated guanidino derivatives are initially forming the mixedanhydride via reaction of the protected alcohol containing acid with achloroformate, such as isobutylchloroformate, in the presence of anon-nucleophilic base, such as triethylamine, in an anhydrous inertsolvent, such as dichloromethane, diethylether or THF. The mixedanhydride is then reacted with the guanidino derivative, preferably inthe presence of a condensation catalyst, such as 4-dimethyl-aminopyridine (DMAP). Alternatively, the protected alcohol containing acidcan first be converted to the acid chloride by treatment with oxalylchloride in the presence of a catalytic amount of DMF. The acid chlorideis then reacted with the guanidino derivative, preferably in thepresence of a condensation catalyst, such as DMAP, and a tertiary aminebase, such as triethylamine, to produce the acylated guanidinoderivative. Alternatively, the protected alcohol containing acid can becoupled to produce the acylated guanidino derivative by treatment with adehydration agent, such as dicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), witha condensation catalyst, such as DMAP. Alternatively the acylating agentmay be reacted with the preformed anion of the guanidino functionalityprepared by deprotonating the guanidino group with a strong base such assodium hydride, lithium hexamethyldisilazide or potassium t-butoxide inan inert solvent such as THF. Preferred protecting groups for thealcohol moiety are silyl ethers, such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent, such as thionyl chloride nitrite, thionyl dinitrite or nitrosiumtetrafluoroborate, in a suitable anhydrous solvent, such asdichlormethane, THF, DMF or acetonitrile, with or without an amine base,such as pyridine or triethylamine, produces the compounds of structureIA.

Nitroso compounds of formula (I) wherein R₁, R₂, R₃, R₆, R₇, R₈ and R₉are as defined herein and a nitrosothiol containing acyl group isrepresentative of the D₁ group as defined herein can be prepared asoutlined in FIG. 2. The guanidino derivative group of structure 1 isconverted to the acylated guanidino derivative of structure 3 byreaction with an appropriate protected thiol containing acid wherein Rand P² are as defined herein. Preferred methods for the preparation ofacylated guanidino derivatives are initially forming the mixed anhydridevia reaction of the acid with a chloroformate, such asisobutylchloroformate, in the presence of a non-nucleophilic base, suchas triethylamine, in an anhydrous inert solvent, such asdichloromethane, diethylether or THF. The mixed anhydride is thenreacted with the guanidino derivative, preferably in the presence of acondensation catalyst, such as DMAP. Alternatively, the acid can firstbe converted to the acid chloride by treatment with oxalyl chloride inthe presence of a catalytic amount of DMF. The acid chloride is thenreacted with the guanidino derivative preferably in the presence of acondensation catalyst, such as DMAP, and a tertiary amine base, such astriethylamine, to produce the acylated guanidino derivative.Alternatively, the protected thiol containing acid and guanidinoderivative can be coupled to produce the acylated guanidino derivativeby treatment with a dehydration agent, such as DCC or EDC, with acondensation catalyst, such as DMAP. Alternatively, the acylating agentmay be reacted with the preformed anion of the guanidino functionalityprepared by deprotonating the guanidino group with a strong base such assodium hydride, lithium hexamethyldisilazide or potassium t-butoxide inan inert solvent such as THF. Preferred protecting groups for the thiolmoiety are as a thioester, such as thioacetate or thiobenzoate, as adisulfide, as a thiocarbamate, such as N-methoxy-methyl thiocarbamate,or as a thioether, such as paramethoxybenzyl thioether, a2,4,6-trimethoxybenzyl thioether, a tetrahydropyranyl thioether, or aS-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenyl-phosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically used to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a 2,4,6-trimethoxybenzyl thioethera tetrahydropyranyl thioether or a S-triphenylmethyl thioether group)followed by reaction with a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, suchas tert-butyl nitrite, or nitrosium tetrafluoro-borate, in a suitableanhydrous solvent, such as methylene chloride, THF, DMF or acetonitrile,with or without an amine base, such as pyridine or triethylamine,produces the compounds of structure IB. Alternatively, a stoichiometricquantity of sodium nitrite in alcoholic or aqueous acid produces thecompounds of structure IB.

Nitroso compounds of formula (II) wherein B, R₅ and q are as definedherein and a nitrite containing acyl group is representative of the Dgroup as defined herein can be prepared as outlined in FIG. 3. Thealcohol of structure 4 is converted to the ester of structure 5 byreaction with an appropriate protected alcohol containing acid wherein Rand P¹ are as defined herein. Preferred methods for the preparation ofesters are initially forming the mixed anhydride via reaction of theacid with a chloroformate, such as isobutylchloroformate, in thepresence of a non-nucleophilic base, such as triethylamine, in ananhydrous inert solvent, such as dichloromethane, diethylether or THF.The mixed anhydride is then reacted with the alcohol, preferably in thepresence of a condensation catalyst, such as DMAP. Alternatively, theacid can first be converted to the acid chloride by treatment withoxalyl chloride in the presence of a catalytic amount of DMF. The acidchloride is then reacted with the hydroxyl group, preferably in thepresence of a condensation catalyst, such as DMAP, and a tertiary aminebase, such as triethylamine, to produce the ester. Alternatively, theprotected alcohol containing acid can be coupled to produce the ester bytreatment with a dehydration agent, such as DCC or EDC, with or withouta condensation catalyst, such as DMAP. Preferred protecting groups forthe alcohol moiety are silyl ethers, such as a trimethylsilyl or atert-butyldimethyl-silyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent, such as thionyl chloride nitrite, thionyl dinitrite or nitrosiumtetrafluoroborate, in a suitable anhydrous solvent, such asdichlormethane, THF, DMF or acetonitrile, with or without an amine base,such as pyridine or triethylamine, produces the compounds of formulaIIA.

Nitroso compounds of formula (II) wherein B, R₅ and q are as definedherein and a nitrosothiol containing acyl group is representative of theD group as defined herein can be prepared as outlined in FIG. 4. Thealcohol of structure 4 is converted to the ester of structure 6 byreaction with an appropriate protected thiol containing acid wherein Rand P² are as defined herein. Preferred methods for the preparation ofesters are initially forming the mixed anhydride via reaction of theacid with a chloroformate, such as isobutylchloroformate, in thepresence of a non-nucleophilic base, such as triethylamine, in ananhydrous inert solvent, such as dichloromethane, diethylether or THF.The mixed anhydride is then reacted with the hydroxyl group, preferablyin the presence of a condensation catalyst, such as DMAP. Alternatively,the acid can first be converted to the acid chloride by treatment withoxalyl chloride in the presence of a catalytic amount of DMF. The acidchloride is then reacted with the hydroxyl moiety, preferably in thepresence of a condensation catalyst, such as DMAP, and a tertiary aminebase, such as triethylamine, to produce the ester. Alternatively, theprotected thiol containing acid and alcohol can be coupled to producethe ester by treatment with a dehydration agent, such as DCC or EDC withor without a condensation catalyst such as DMAP. Preferred protectinggroups for the thiol moiety are as a disulfide, or as a thioether, suchas paramethoxybenzyl thioether, a 2,4,6-trimethoxybenzyl thioether, atetrahydropyranyl thioether, or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenyl-phosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while mercuric trifluoroacetate,silver nitrate or strong acids such as trifluoroacetic or hydrochloricacid and heat are used to remove a paramethoxybenzyl thioether, a2,4,6-trimethoxybenzyl thioether a tetrahydro-pyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent, such as thionyl chloride nitrite, thionyldinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, produces the compounds ofstructure IIB. Alternatively, a stoichiometric quantity of sodiumnitrite in alcoholic or aqueous acid produces the compounds of structureIIB.

Nitroso compounds of formula (III) wherein B and R₄ are as definedherein and a nitrite containing acyl group is representative of the D₁group as defined herein can be prepared as outlined in FIG. 5. Theguanidino derivative of formula 7 is converted to the acylated guanidinoderivative of structure 8 by reaction with an appropriate protectedalcohol containing acid wherein R and P¹ are as defined herein.Preferred methods for the preparation of acylated guanidino derivativesare initially forming the mixed anhydride via reaction of the protectedalcohol containing acid with a chloroformate, such asisobutylchloroformate, in the presence of a non-nucleophilic base, suchas triethylamine, in an anhydrous inert solvent, such asdichloromethane, diethylether or THF. The mixed anhydride is thenreacted with the guanidino derivative, preferably in the presence of acondensation catalyst, such as DMAP. Alternatively, the protectedalcohol containing acid can first be converted to the acid chloride bytreatment with oxalyl chloride in the presence of a catalytic amount ofDMF. The acid chloride is then reacted with the guanidino derivative,preferably in the presence of a condensation catalyst, such as DMAP, anda tertiary amine base, such as triethylamine, to produce the acylatedguanidino derivative. Alternatively, the protected alcohol containingacid can be coupled to produce the acylated guanidino derivative bytreatment with a dehydration agent, such as DCC or EDC, with or withouta condensation catalyst, such as DMAP. Alternatively, the acylatingagent may be reacted with the preformed anion of the guanidinofunctionality prepared by deprotonating the guanidino group with astrong base such as sodium hydride, lithium hexamethyldisilazide orpotassium t-butoxide in an inert solvent such as THF. Preferredprotecting groups for the alcohol moiety are silyl ethers, such as atrimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of thehydroxyl moiety (fluoride ion is the preferred method for removing silylether protecting groups) followed by reaction with a suitablenitrosylating agent, such as thionyl chloride nitrite, thionyl dinitriteor nitrosium tetrafluoroborate, in a suitable anhydrous solvent, such asdichlormethane, THF, DMF or acetonitrile, with or without an amine base,such as pyridine or triethylamine, produces the compounds of structureIIIA.

Nitroso compounds of formula (III) wherein B and R₄ are as definedherein and a nitrosothiol containing acyl group is representative of theD₁ group as defined herein can be prepared as outlined in FIG. 6. Theguanidino derivative group of structure 7 is converted to the acylatedguanidino derivative of structure 9 by reaction with an appropriateprotected thiol containing acid wherein R and P2 are as defined herein.Preferred methods for the preparation of acylated guanidino derivativesare initially forming the mixed anhydride via reaction of the acid witha chloroformate, such as isobutylchloroformate, in the presence of anon-nucleophilic base, such as triethylamine, in an anhydrous inertsolvent, such as dichloromethane, diethylether or THF. The mixedanhydride is then reacted with the guanidino derivative, preferably inthe presence of a condensation catalyst, such as DMAP. Alternatively,the acid can first be converted to the acid chloride by treatment withoxalyl chloride in the presence of a catalytic amount of DMF. The acidchloride is then reacted with the guanidino derivative preferably in thepresence of a condensation catalyst, such as DMAP, and a tertiary aminebase, such as triethyl-amine, to produce the acylated guanidinoderivative. Alternatively, the protected thiol containing acid andguanidino derivative can be coupled to produce the acylated guanidinoderivative by treatment with a dehydration agent, such as DCC or EDCwith or without a condensation catalyst such as DMAP. Alternatively, theacylating agent may be reacted with the preformed anion of the guanidinofunctionality prepared by deprotonating the guanidino group with astrong base such as sodium hydride, lithium hexamethyldisilazide orpotassium t-butoxide in an inert solvent such as THF. Preferredprotecting groups for the thiol moiety are as a thioester, such asthioacetate or thiobenzoate, as a disulfide, as a thiocarbamate, such asN-methoxy-methyl thiocarbamate, or as a thioether, such asparamethoxybenzyl thioether, a 2,4,6-trimethoxybenzyl thioether, atetrahydropyranyl thioether, or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenyl-phosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while aqueous base is typicallyused to hydrolyze thioesters and N-methoxymethyl thiocarbamates andmercuric trifluoroacetate, silver nitrate or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a 2,4,6-trimethoxybenzyl thioether atetrahydropyranyl thioether or a S-triphenylmethyl thioether group)followed by reaction with a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, suchas tert-butyl nitrite, or nitrosium tetrafluoro-borate, in a suitableanhydrous solvent, such as methylene chloride, THF, DMF or acetonitrile,with or without an amine base, such as pyridine or triethylamine,produces the compounds of structure IIIB. Alternatively, astoichiometric quantity of sodium nitrite in alcoholic or aqueous acidproduces the compounds of structure IIIB.

The compounds of the present invention include H₂ receptor antagonists,such as those described herein, which have been nitrosylated through oneor more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydrylcondensation), carbon and/or nitrogen. The nitrosated and/ornitrosylated H₂ receptor antagonists of the present invention arecapable of donating, transfering and/or releasing a biologically activeform of nitrogen monoxide (i.e., nitric oxide).

Nitrogen monoxide can exist in three forms: NO⁻ (nitroxyl), NO.(uncharged nitric oxide) and NO⁺ (nitrosonium). NO. is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO.),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO⁻ arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

Compounds contemplated for use in the present invention (e.g., H₂receptor antagonists optionally substituted with one or more NO and/orNO₂ groups) are, optionally, used in combination with nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer a biologically active form of nitrogen monoxide to asite of its intended activity, such as on a cell membrane in vivo.

The term “nitric oxide” encompasses uncharged nitric oxide (NO.) andcharged nitrogen monoxide species, preferably charged nitrogen monoxidespecies, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO⁻). Thereactive form of nitric oxide can be provided by gaseous nitric oxide.The nitrogen monoxide releasing, delivering or transferring compoundshave the structure F—NO, wherein F is a nitrogen monoxide releasing,delivering or transferring moiety, and include any and all suchcompounds which provide nitrogen monoxide to its intended site of actionin a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates),(E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides,nitrosoamines, furoxans as well as substrates for the endogenous enzymeswhich synthesize nitric oxide. The “NO adducts” can bemono-nitrosylated, poly-nitrosylated, mono-nitrosated and/orpoly-nitrosated or any combination thereof at a variety of naturallysusceptible or artificially provided binding sites for biologicallyactive forms of nitrogen monoxide.

One group of NO adducts is the S-nitrosothiols, which are compounds thatinclude at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof; S-nitrosylated sugars; S-nitrosylated, modifiedand unmodified, oligonucleotides (preferably of at least 5, and morepreferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

Another embodiment of the present invention is S-nitroso amino acidswhere the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine and S-nitroso-glutathione.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins; heme proteins,such as hemoglobin and serum albumin; and biologically protectiveproteins, such as immunoglobulins, antibodies and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

Other examples of suitable S-nitrosothiols include:

(i) HS(C(R_(e))(R_(f)))_(m)SNO;

(ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); and

(iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

wherein m is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl,a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, anamino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, acarboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, acarboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid,an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, a carbamoyl, aurea, a nitro, —T—Q, or (C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f)taken together with the carbon atoms to which they are attached are acarbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or abridged cycloalkyl group; Q is —NO or —NO₂; and T is independently acovalent bond, a carbonyl, an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—,wherein o is an integer from 0 to 2, R_(a) is a lone pair of electrons,a hydrogen or an alkyl group; R_(i) is a hydrogen, an alkyl, an aryl, analkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester,an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, analkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, anarylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an amino aryl, —CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺,wherein M⁺ is an organic or inorganic cation; with the proviso that whenR_(i) is —CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂—).M⁺; then “—T—Q” can be ahydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group.

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical wherein R_(i)is as defined herein.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

Another group of NO adducts for use in the present invention, where theNO adduct is a compound that donates, transfers or releases nitricoxide, include compounds comprising at least one ON—O—, ON—N— or ON—C—group. The compounds that include at least one ON—O—, ON—N— or ON—C—group are preferably ON—O—, ON—N— or ON—C-polypeptides (the term“polypeptide” includes proteins and polyamino acids that do not possessan ascertained biological function, and derivatives thereof); ON—O,ON—N— or ON—C-amino acids (including natural and synthetic amino acidsand their stereoisomers and racemic mixtures); ON—O—, ON—N— orON—C-sugars; ON—O—, ON—N— or ON—C— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O—, ON—N— or ON—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

Another group of NO adducts for use in the present invention includenitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C—group. Preferred among these compounds are O₂N—O—, O₂N—N—, O₂N—S— orO₂N—C— polypeptides (the term “polypeptide” includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C-sugars; O₂N—O—,O₂N—N—, O₂N—S— or O₂N—C— modified and unmodified oligonucleotides(comprising at least 5 nucleotides, preferably 5-200 nucleotides);O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group include isosorbide dinitrate,isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitolhexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitroland propatylnitrate.

Another group of NO adducts are N-oxo-N-nitrosoamines that donate,transfer or release nitric oxide and are represented by the formula:R¹R²N—N(O—M⁺)—NO, where R¹ and R² are each independently a polypeptide,an amino acid, a sugar, a modified or unmodified oligonucleotide, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andM⁺ is as defined herein

Another group of NO adducts are thionitrates that donate, transfer orrelease nitric oxide and are represented by the formula: R¹—(S)—NO₂,where R¹ is a polypeptide, an amino acid, a sugar, a modified orunmodified oligonucleotide, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbon, or a heterocyclic group. Preferred are those compoundswhere R¹ is a polypeptide or hydrocarbon with a pair or pairs of thiolsthat are sufficiently structurally proximate, i.e., vicinal, that thepair of thiols will be reduced to a disulfide. Compounds which formdisulfide species release nitroxyl ion (NO⁻) and uncharged nitric oxide(NO.). Compounds where the thiol groups are not sufficiently close toform disulfide bridges generally provide nitric oxide as the NO⁻ formand not as the uncharged NO. form.

The present invention is also directed to compounds that stimulateendogenous NO or elevate levels of endogenous endothelium-derivedrelaxing factor (EDRF) in vivo or are substrates for nitric oxidesynthase. Such compounds include, for example, L-arginine,L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine, and/or nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, ornithineor glutamine, inhibitors of the enzyme arginase (e.g.,N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and thesubstrates for nitric oxide synthase, cytokines, adenosin, bradykinin,calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascularrelaxing factor secreted by the endothelium, and has been identified asnitric oxide (NO) or a closely related derivative thereof (Palmer et al,Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA,84:9265-9269 (1987)).

Another aspect of the present invention provides methods to decrease orreverse gastrointestinal toxicity and facilitate ulcer healing resultingfrom the administration of nonsteroidal antiinflammatory drugs (NSAIDs)to a patient. In particular, the present invention provides methods ofadministering a therapeutically effective amount of at least one NSAIDwith a therapeutically effective amount of the compounds and/orcompositions described herein. In one aspect of the invention, thepatient can be administered at least one NSAID with a therapeuticallyeffective amount of at least one nitrosated and/or nitrosylated H₂receptor antagonist of the invention to decrease or reversegastrointestinal toxicity and/or to facilitate ulcer healing resultingfrom NSAID treatment. In another aspect of the invention, the patientcan be administered at least one NSAID with a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated H₂ receptorantagonist of the invention and at least one compound that donates,transfers or releases nitric oxide, or elevates endogenous levels ofnitric oxide or EDRF, or is a substrate for nitric oxide synthase, todecrease or reverse gastrointestinal toxicity and/or to facilitate ulcerhealing resulting from NSAID treatment. In yet another aspect of thepresent invention, the patient can be administered at least one NSAIDwith a therapeutically effective amount of at least one H₂ receptorantagonist and at least one compound that donates, transfers or releasesnitric oxide, or elevates endogenous levels of nitric oxide or EDRF, oris a substrate for nitric oxide synthase, to decrease or reversegastrointestinal toxicity and/or to facilitate ulcer healing resultingfrom NSAID treatment. The NSAID, nitrosated and/or nitrosylated H₂receptor antagonist, H₂ receptor antagonist, and/or nitric oxide donorcan be administered separately or as components of the same composition.These compounds and/or compositions can also be provided in the form ofa pharmaceutical kit.

The compounds and compositions of the present invention can be used inthis aspect of the invention with any NSAID known in the art. SuchNSAIDs include, for example, aspirin (e.g., acetylsalicylic acid),salicylate esters and salts, acetate esters of salicylic acid,diflurophenyl derivatives (e.g., diflunisal), salicylsalicylic acids(e.g., salsalate), salts of salicylic acids (e.g., sodium salicylate),salicylamide, sodium thiosalicylate, choline salicylate, magnesiumsalicylate, combinations of choline and magnesium salicylates,5-aminosalicylic acid (e.g., mesalamine), salicylazosulfapyridine (e.g.,sulfasalazine), methylsalicylate, and the like.

Another group of NSAIDs are the pyrazolon derivatives, which include,for example, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,dipyrone and apazone (azapropazone). Another group of NSAIDs are thepara-aminophenol derivatives, which are the so-called “coal tar”analgesics, including, for example, phenacetin and its active metaboliteacetaminophen. Another group of compounds include indomethacin, amethylated indole derivative, and the structurally related compoundsulindac. Yet another group of compounds is the fenamates which arederivatives of N-phenylanthranilic acid (e.g., mefenamic, meclofenamic,flufenamic, tolfenamic and etofenamic acids). Another contemplated NSAIDis tolmetin.

Another group of NSAIDs are the propionic acid derivatives. Principalmembers of this group are, for example, ibuprofen, naproxen,flurbiprofen, fenoprofen and ketoprofen. Other members of this groupinclude, for example, fenbufen, pirprofen, oxaprozin, indoprofen andtiaprofenic acid.

Still other NSAIDs are piroxicam, ampiroxicam, oxicam derivatives (whichare a class of antiinflammatory enolic acids), tenoxicam tenidap,diclofenac (one of the series of phenylacetic acid derivatives that havebeen developed as antiinflammatory agents). Other NSAIDs includeetodolac and nabumentone.

Each of the above contemplated NSAIDs is described more fully in theliterature, such as in Goodman and Gilman, The Pharmacological Basis ofTherapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617-657; the MerckIndex on CD-ROM, Twelfth Edition, Version 12:1, 1996.

Other NSAIDs that can be used in the present invention include thosedescribed in U.S. Pat. No. 5,703,073, the disclosure of which isincorporated by reference herein in its entirety.

Another aspect of the present invention provides methods to improve thegastroprotective properties, anti-Helicobacter properties and antacidproperties of H₂ receptor antagonists by administering to a patient inneed thereof a therapeutically effective amount of the compounds and/orcompositions described herein. In one aspect of the invention, thepatient can be administered at least one nitrosated and/or nitrosylatedH₂ receptor antagonist of the invention to improve the gastroprotectiveproperties, anti-Helicobacter properties and antacid properties of theH₂ receptor antagonist. In another aspect of the invention, the patientcan be administered a bismuth-complex comprising at least one nitrosatedand/or nitrosylated H₂ receptor antagonist of the invention to improvethe gastroprotective properties, anti-Helicobacter properties andantacid properties of the H₂ receptor antagonist. In another aspect ofthe invention, the patient can be administered at least one nitrosatedand/or nitrosylated H₂ receptor antagonist of the invention and at leastone compound that donates, transfers or releases nitric oxide, orelevates endogenous levels of nitric oxide or EDRF, or is a substratefor nitric oxide synthase, to improve the gastroprotective properties,anti-Helicobacter properties and antacid properties of the H₂ receptorantagonist. In another aspect of the invention, the patient can beadministered a bismuth complex comprising at least one nitrosated and/ornitrosylated H₂ receptor antagonist of the invention and at least onecompound that donates, transfers or releases nitric oxide, or elevatesendogenous levels of nitric oxide or EDRF, or is a substrate for nitricoxide synthase, to improve the gastroprotective properties,anti-Helicobacter properties and antacid properties of the H₂ receptorantagonist. In yet another aspect of the invention, the patient can beadministered at least one H₂ receptor antagonist and at least onecompound that donates, transfers or releases nitric oxide, or elevatesendogenous levels of nitric oxide or EDRF, or is a substrate for nitricoxide synthase, to improve the gastroprotective properties,anti-Helicobacter properties and antacid properties of the H₂ receptorantagonist. In yet another aspect of the present invention, the patientcan be administered a bismuth-complex comprising at least one H₂receptor antagonist and at least one compound that donates, transfers orreleases nitric oxide, or elevates endogenous levels of nitric oxide orEDRF, or is a substrate for nitric oxide synthase, to improve thegastroprotective properties, anti-Helicobacter properties and antacidproperties of the H₂ receptor antagonist.

The bismuth-containing reagent, H₂ receptor antagonist, that isoptionally, substituted with at least one NO and/or NO₂ group, andnitric oxide donor can be administered separately or as components ofthe same composition. The H₂ receptor antagonists, optionallysubstituted with at least one NO and/or NO₂ group, and nitric oxidedonors are described in detail herein. Bismuth complexes are prepared byboiling the aqueous solution of the free base of the H₂ receptorantagonist with at least one bismuth containing reagent, including, forexample, bismuth citrate, bismuth salicylate, bismuth tartaric acid ormixtures thereof.

Another aspect the invention provides methods for preventing or treatinggastrointestinal disorders by administering to the patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Such gastrointestinal disorders include,for example, peptic ulcers, stress ulcers, gastric hyperacidity,dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophagealreflux disease, short-bowel (anastomosis) syndrome, hypersecretorystates associated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. In oneaspect of the invention, the patient can be administered at least onenitrosated and/or nitrosylated H₂ receptor antagonist of the inventionto prevent or treat the gastrointestinal disorder. In another aspect ofthe invention, the patient can be administered at least one antacid andat least one nitrosated and/or nitrosylated H₂ receptor antagonist ofthe invention to prevent or treat the gastrointestinal disorder. Inanother aspect of the invention, the patient can be administered atleast one nitrosated and/or nitrosylated H₂ receptor antagonist of theinvention and at least one compound that donates, transfers or releasesnitric oxide, or elevates endogenous levels of nitric oxide or EDRF, oris a substrate for nitric oxide synthase, to prevent or treat thegastrointestinal disorder. In still another aspect of the invention, thepatient can be administered at least one antacid, at least onenitrosated and/or nitrosylated H₂ receptor antagonist of the invention,and at least one compound that donates, transfers or releases nitricoxide, or elevates endogenous levels of nitric oxide or EDRF, or is asubstrate for nitric oxide synthase, to prevent or treat thegastrointestinal disorder. In yet another aspect of the presentinvention, the patient can be administered at least one H₂ receptorantagonist and at least one compound that donates, transfers or releasesnitric oxide, or elevates endogenous levels of nitric oxide or EDRF, oris a substrate for nitric oxide synthase, to prevent or treat thegastrointestinal disorder. In yet another aspect of the presentinvention, the patient can be administered at least one antacid, atleast one H₂ receptor antagonist, and at least one compound thatdonates, transfers or releases nitric oxide, or elevates endogenouslevels of nitric oxide or EDRF, or is a substrate for nitric oxidesynthase, to prevent or treat the gastrointestinal disorder.

The antacid, H₂ antagonist that is optionally substituted with at leastone NO and/or NO₂ group, and the nitric oxide donor can be administeredseparately or as components of the same composition. These compoundsand/or compositions can also be provided in the form of a pharmaceuticalkit. The H₂ receptor antagonists substituted with at least one NO and/orNO₂ group and preferred nitric oxide donors are described in detailherein. Appropriate antacids for use in this aspect of the inventioninclude any antacid known in the art, including, for example, aluminumhydroxide, magnesium hydroxide, magnesium carbonate, calcium carbonateand co-dried gels, such as, for example, aluminum hydroxide-magnesiumcarbonate co-dried gel.

Another aspect of the present invention provides methods for preventingand treating inflammations and/or microbial infections by administeringthe compounds and/or compositions described herein. The inflammationsand/or microbial infections that are being prevented or treated arepreferably those of the eyes, ears, nose or skin. In one aspect of theinvention, the patient can be administered at least one nitrosatedand/or nitrosylated H₂ receptor antagonist of the invention to treat theinflammation or microbial infection. In another aspect of the invention,the patient can be administered at least one nitrosated and/ornitrosylated H₂ receptor antagonist of the invention and at least onecompound that donates, transfers or releases nitric oxide, or elevatesendogenous levels of nitric oxide or EDRF, or is a substrate for nitricoxide synthase, to treat the inflammation or microbial infection. In yetanother aspect of the present invention, the patient can be administeredat least one H₂ receptor antagonist and at least one compound thatdonates, transfers or releases nitric oxide, or elevates endogenouslevels of nitric oxide or EDRF, or is a substrate for nitric oxidesynthase, to treat the inflammation or microbial infection. The H₂receptor antagonist that is optionally substituted with at least one NOand/or NO₂ group and the nitric oxide donor can be administeredseparately or as components of the same composition.

Another aspect of the present invention provides methods for preventingand treating ophthalmic diseases and disorders by administering thecompounds and/or compositions described herein. The ophthalmic diseasesand disorders include glaucoma, inflammation of the eye and elevation ofintraocular pressure. In one aspect of the invention, the patient can beadministered at least one nitrosated and/or nitrosylated H₂ receptorantagonist of the invention to treat the ophthalmic diseases anddisorders. In another aspect of the invention, the patient can beadministered at least one nitrosated and/or nitrosylated H₂ receptorantagonist of the invention and at least one compound that donates,transfers or releases nitric oxide, or elevates endogenous levels ofnitric oxide or EDRF, or is a substrate for nitric oxide synthase, totreat the ophthalmic diseases and disorders. In yet another aspect ofthe present invention, the patient can be administered at least one H₂receptor antagonist and at least one compound that donates, transfers orreleases nitric oxide, or elevates endogenous levels of nitric oxide orEDRF, or is a substrate for nitric oxide synthase, to treat theophthalmic diseases and disorders. The H₂ receptor antagonist that isoptionally substituted with at least one NO and/or NO₂ group and thenitric oxide donor can be administered separately or as components ofthe same composition.

Another aspect the present invention provides methods for treatingmultiple sclerosis, and viral infections, such as HIV disease, byadministering to the patient a therapeutically effective amount of thecompounds and/or compositions described herein. In one aspect of theinvention, the patient can be administered at least one nitrosatedand/or nitrosylated H₂ receptor antagonist of the invention to treatmultiple sclerosis or the viral infection. Treating a viral infectioncan further comprise administering at least one anti-viral agent to thepatient. In another aspect of the invention, the patient can beadministered at least one nitrosated and/or nitrosylated H₂ receptorantagonist of the invention, at least one compound that donates,transfers or releases nitric oxide, or elevates endogenous levels ofnitric oxide or EDRF, or is a substrate for nitric oxide synthase, totreat multiple sclerosis or the viral infection. Treating a viralinfection can further comprise administering at least one anti-viralagent to the patient. In yet another aspect of the present invention,the patient can be administered at least one H₂ receptor antagonist andat least one compound that donates, transfers or releases nitric oxide,or elevates endogenous levels of nitric oxide or EDRF, or is a substratefor nitric oxide synthase, to treat multiple sclerosis or the viralinfection. Treating a viral infection can further comprise administeringat least one anti-viral agent to the patient.

The H₂ receptor antagonist that is substituted with at least one NOand/or NO₂ group, the anti-viral agents, and the nitric oxide donor canbe administered separately or as components of the same composition. TheH₂ receptor antagonists substituted with at least one NO and/or NO₂group and preferred nitric oxide donors are described in detail above.Appropriate anti-viral agents include any anti-viral agent known in theart, including, for example, metronidazole, AZT (3′-azidothymidine), DDI(2′,3′-dideoxyinosine), DDC (2′,3′-dideoxycytidine), L-735,524(N-(2-(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N′-(butylcarboxamido)-piperazinyl))-pentaneamide),and the like. These compounds and/or compositions can also be providedin the form of a pharmaceutical kit. Preferred H₂ receptor antagonists,including those that are substituted with at least one NO and/or NO₂group, and preferred nitric oxide donors are described in detail herein.

When administered in vivo, the compounds and compositions of the presentinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. While the compoundsand compositions of the invention can be administered as a mixture of anH₂ receptor antagonist that is optionally substituted with at least oneNO and/or NO₂ group and a nitric oxide donor, they can also be used incombination with one or more additional compounds (e.g., NSAIDs,antacids, bismuth-containing reagents, anti-viral agents) which areknown to be effective against the specific disease state that one istargeting for treatment. The nitric oxide donor(s) can be administeredsimultaneously with, subsequently to, or prior to administration of theH₂ receptor antagonist that is optionally substituted with at least oneNO and/or NO₂ group, and/or other additional compounds.

The compounds and compositions of the present invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.,by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. Parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of the presentinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention, such as for treating pediatric fever andthe like, can be prepared by mixing the compounds or compositions with asuitable nonirritating excipient such as cocoa butter and polyethyleneglycols which are solid at room temperature but liquid at rectaltemperature, such that they will melt in the rectum and release thedrug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, surfactants, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the present invention, including, forexample, encapsulation in liposomes, microbubbles, emulsions,microparticles, microcapsules and the like.

The bioavailabilty of the compositions can be enhanced by micronizationof the formulations using conventional techniques such as grinding,milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

The compounds and compositions of the present invention can beformulated as neutral or pharmaceutically acceptable salt forms.Pharmaceutically acceptable salts include, for example, those formedwith free amino groups such as those derived from hydrochloric,hydrobromic, phosphoric, sulfuric, acetic, citric, benzoic, fumaric,glutamic, lactic, malic, maleic, nitric, succinic, tartaricp-toluene-sulfonic, methanesulfonic, acids, gluconic acid, and the like,and those formed with free carboxyl groups such as those derived fromsodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine,triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

“Therapeutically effective amount” refers to the amount of the H₂receptor antagonist that is optionally substituted with at least one NOand/or NO₂ group, and nitric oxide donor that is effective to achieveits intended purpose. While individual patient needs may vary,determination of optimal ranges for effective amounts of each of thecompounds and compositions is within the skill of the art. Generally,the dosage required to provide an effective amount of the composition,and which can be adjusted by one of ordinary skill in the art will vary,depending on the age, health, physical condition, sex, weight, extent ofthe dysfunction of the recipient, frequency of treatment and the natureand scope of the dysfunction or disease.

The amount of a given H₂ receptor antagonist that is optionallysubstituted with at least one NO and/or NO₂ group which will beeffective in the treatment of a particular disorder or condition willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques, including reference to Goodman andGilman, supra; The Physician's Desk Reference, Medical EconomicsCompany, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons,Inc., St. Louis, Mo., 1993. The precise dose to be used in theformulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided by thephysician and the patient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of the H₂receptor antagonist. The usual daily doses of H₂ receptor antagonistsare about 1 mg to about 10 g per day and the doses of nitric oxidedonors in the pharmaceutical composition can be in amounts of about0.001 mg to about 40 g, while that actual amount will be dependent uponthe specific nitric oxide donor. Effective doses may be extrapolatedfrom dose-response curves derived from in vitro or animal model testsystems and are in the same ranges or less than as described for thecommercially available compounds in the Physician's Desk Reference,supra.

The present invention also provides pharmaceutical kits comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the present invention,including, at least, one or more of the H₂ receptor antagonists, thatare optionally substituted with at least one NO and/or NO₂ group,described herein and one or more of the NO donors described herein.Associated with such kits can be additional compounds or compositions(e.g., NSAIDs, antacids, bismuth-containing reagents, anti-viral agents,permeation enhancers, lubricants, and the like), devices foradministering the compositions, and notices in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products which reflects approval by theagency of manufacture, use or sale for humans.

EXAMPLES

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the present invention. In eachof the examples, flash chromatography was performed on 40 micron silicagel (Baker).

Example 1(2Z)-2-aza-3-(methylamino)-3-({2-[(5-methyl-1-{2-[2-(nitrosothio)adamantan-2-yl]acetyl}imidazol-4-yl)methylthio]ethyl}amino)prop-2-enenitrile

1a. adamantane-2-thione

Adamantan-2-one (48.46 g, 322.6 mmol) in pyridine (300 mL) was heated to90° C., and phosphorous pentasulfide (17.84 g, 40.13 mmol) was added.The reaction was maintained at 90° C. for two hours, and at roomtemperature overnight, during which time a precipitate formed. Thepyridine solution was decanted and concentrated to dryness. The residualsemisolid was treated with hexane (400 mL) to give an orange solutionwith a light brown suspension. The suspension was removed by filtration.The filtrate was concentrated to dryness and dried under vacuum to givean orange solid (50.36 g). This crude product was purified by filtrationthrough a pad of silica gel (hexane). ¹H NMR (300 MHz, CDCl₃): δ3.43 (s,2H), 2.1-1.9 (m, 12H). ¹³C NMR (75 MHz, CDCl₃): δ222.4, 57.5, 41.1,36.5, 27.4.

1b. tert-butyl 2-(2-sulfanyladamantan-2-yl)acetate

To t-butyl acetate (25 mL, 21.6 g, 186 mmol) in dry THF (400 mL) at −78°C. was added lithium diisopropylamide monotetrahydrofuran (1.5 Msolution in cyclohexane, 100 mL, 150 mmol) under nitrogen. It wasstirred at −78° C. for 40 minutes. The product of Example 1a (21.88 g,131.57 mmol) in THF (400 mL) was added. The cold bath was removed andthe reaction was stirred at room temperature for two hours. The reactionwas diluted with methylene chloride, and 2 M HCl (75 mL) was added. Theorganic phase was separated, washed with brine (4×40 mL), dried (MgSO₄),filtered, and concentrated. The crude product was purified by filtrationthrough a pad of silica gel (5% EtOAc/95% hexane) to give the titlecompound (34.67 g, 122.7 mmol, 93%). R_(f)=0.48 (EtOAc/hexane 1:19). ¹HNMR (300 MHz, CDCl₃): δ2.87 (s, 2H), 2,47 (d, J=11.5, 2H), 2.38 (s, 1H),2.11 (d, J=11.9, 2H), 1.98 (s, 2H), 1.96 (m, 2H), 1.84-1.696 (m, 6H),1.47 (s, 9H). ¹³C NMR (75 MHz, CDCl₃): δ170.8, 80.7, 54.1, 47.3, 39.0,38.2, 37.2, 36.6, 34.0, 33.3,28.2,27.5,26.9. APIMS (IS, NH₄OAc) m/e 283(MH⁺). Anal. Calcd. for C₁₆H₂₆0₂S (282.44): C, 68.04; H, 9.28. Found: C,68.14; H, 9.30.

1c. 2-(2-sulfanyladamantan-2-yl)acetic acid

To the product of Example 1b (10.76 g, 38.1 mmol) in methylene chloride(15 ml) was added trifluoroacetic acid (TFA) (15 mL). The reaction wasstirred at room temperature for 40 minutes and concentrated to dryness.The residue was treated with methylene chloride and concentrated todryness three times. The residual solid was triturated with methylenechloride (20 ml). Solid was collected by filtration, washed with a smallamount of methylene chloride, and dried in vacuum to give the titlecompound (5.6447 g, 24.94 mmol, 65%). ¹H NMR (300 MHz, CDCl₃): δ9.5(broad, 1H), 3.04 (s, 2H), 2.49 (d, J=11.2, 2H), 2.25 (s, 1H), 2.1-2.0(m, 4H), 1.9 (m, 2H), 1.7-1.6 (m, 6H). ¹³C NMR (75 MHz, CDCl₃): δ177.7,53.4, 46.3, 38.9, 37.8, 33.8, 33.2, 27.4, 26.8. APIMS (IS, NH₄OAc) m/e225 (M-H⁺). Anal. Calcd for C₁₂H₁₈0₂S (226.33): C, 63.68; H, 8.02.Found: C, 63.40; H, 7.90.

1d. 2-[2-(nitrosothio)adamantan-2-yl]acetic acid

The product of Example 1c (773.1 mg, 3.416 mmol) was dissolved in hotmethylene chloride (40 mL). The methylene chloride solution was cooledto room temperature and t-butyl nitrite (420 mL, 370 mg, 3.59 mmol) wasadded. The reaction immediately turned green and was stirred at roomtemperature for 30 minutes. Some methylene chloride (15 mL) wasevaporated at reduced pressure to give a suspension. This suspension wasstored in refrigerator over the weekend and purified by columnchromatography (silica gel, 25% EtOAc/75% hexane) to give the titlecompound (628.2 mg, 2.46 mmol, 72%). ¹H NMR (300 MHz, CDCl₃): δ10.8(broad, 1H), 3.77 (s, 2H), 2.78 (s, 2H), 2.4 (m, 2H), 2.1-1.7 (m, 10H).¹³C NMR (75 MHz, CDCl₃): δ177.0, 65.2, 42.1, 38.8, 35.4, 33.7, 33.1,27.1. APIMS (IS, NH₄OAc) m/e 254 (M-H⁺).

1e.(2Z)-2-aza-3-(methylamino)-3-({2-[(5-methyl-1-{2-[2-(nitrosothio)-adamant-2yl]acetyl}imidazol-4-yl)methylthio]ethyl}amino)prop-2-enenitrile

To an ice-cooled suspension of the product of Example 1d (2.16 g, 8.46mmol) and(2Z)-2-aza-3-(methylamino)-3-({2-[(5-methylimidazol-4-yl)methylthio]ethyl}amino)prop-2-enenitrile(2.34 g, 9.27 mmol) in dichloromethane (90 mL) was added a solution of 1M 1,3-dicyclohexylcarbodiimide (DCC) in dichioromethane (10.7 ml, 10.7mmol). After 30 minutes, the reaction was warmed to room temperature andstirred for 1 hour. To the reaction was added water (100 ml). Afterseparation of layers, the aqueous layer was extracted by dichloromethane(2×50 ml). The combined organic layers were dried with sodium sulfateand evaporated to dryness. The residue was purified by flashchromatography (SiO₂, ethyl acetate followed by 3-5% methanol/ethylacetate). The title compound was obtained as a green foam (1.10 g,26.5%). Rf=0.58 (SiO₂, 10% methanol in ethyl acetate); ¹H NMR (300 MHz,CDCl₃): δ1.79-2.12 (m, 10 H), 2.33 (s, 3H), 2.47 (d, J=13.1 Hz, 2 H),2.68 (t, J=6.4 Hz, 2H), 2.85 (d, J=4.0 Hz, 3H), 2.96 (s, 2H), 3.43 (d,J=5.7 Hz, 2 H), 3.59 (s, 2 H), 4.40 s, 2 H), 6.59 (s, 1 H), 6.74 (br s,1 H), 7.96 (s, 1 H); ¹³C NMR (75 MHz, CDCl₃): δ11.08, 2.63, 26.67,28.05, 32.88, 33.28, 35.37, 38.29, 40.91, 42.77, 66.00, 118.86, 125.03,135.49, 137.06, 160.16, 167.95; LCMS (m/e): 490 (M⁺).

Example 2 (N-{3-[3-(piperidylmethyl)phenoxy]propyl}carbamoyl)methyl2-[2-(nitrosothio)adamantan-2-yl]acetate

To an ice-cooled solution of the product of Example 1d (0.589 g, 2.31mmol), 2-hydroxy-N-{3-[3-(piperdylmethyl)phenoxy]propyl}acetamide (0.706g, 2.30 mmol) and DMAP (10 mg) in dichioromethane (20 mL) was added asolution of 1 M DCC in dichloromethane (2.5 mL, 2.5 mmol). After 30minutes, the reaction was warmed to room temperature and stirred for 1hour. The reaction was diluted with dichloromethane (30 mL) and washedwith water (30 mL). After drying over sodium sulfate and concentrationunder vacuum, the residue was purified by flash chromatography (SiO₂,10% methanol in ethyl acetate) to afford the title compound as a greenoil (0.45 g, 35.9%). ¹H NMR (300 MHz, CDCl₃): δ1.30-1.35 (m, 2 H),1.55-1.60 (m, 4H), 1.74-2.03 (m, 12 H), 2.34-2.40 (m, 6 H), 2.75 (br s,2 H), 3.44-3.55 (m, 2 H), 3.46 (s, 2H), 3.82 (s, 2 H), 4.03 (t, J=5.9Hz, H), 4.44 (s, 2 H), 6.39 (br t, J=5.0 Hz, 1 H), 6.79 (d, J=7.5 1 H),6.90 (d, J=7.0 Hz, 1 H), 6.92 (s, 1H), 7.20 (t, J=7.9 Hz, 1 H); ¹³C NMR(75 MHz, CDCl₃): δ24.03, 25.52, 26.79, 28.61, 32.88, 33.48, 35.34,36.69, 38.48, 41.83, 54.11, 62.57, 63.34, 65.71, 112.98, 115.07, 121.73,128.86, 139.64, 158.45, 166.67, 168.77; MS (m/e): 544 (M+).

Example 3 (N-3{-[3-(piperidylmethyl)phenoxy]propyl}carbamoyl)methyl3-{N-[2-methyl-2-(nitrosothio)propyl]carbamoyl}propanoate

3a. 3-[N-(2-methyl-2-sulfanylpropyl)carbamoyl]propanoic acid

To an ice-cooled suspension of 1-amino-2-methylpropan2-thiolhydrochloride (5.06 g, 35.72 mmol) in methylene chloride (100 mL) wasadded triethylamine (5.0 mL, 35.87 mmol) followed by succinic anhydride(3.50 g, 34.96 mmol). The resulting clear solution was stirred at 0° C.or 10 minutes, then at room temperature for 2 hours. Evaporation of thevolatiles under reduced pressure gave a residue which was partitionedbetween 2 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). Theaqueous layer was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine (5 mL), dried over sodium sulfateand evaporated to dryness. The residue was triturated with ether-hexaneto afford the title compound as a white solid (6.78 g, 94.4%). Mp.86-87° C.; ¹H NMR (300 MHz, CDCl₃): δ1.34 (s, 6H), 1.55(s, 1H), 2.59 (t,J=6.6 Hz, H), 2.70 (t, J=6.6 Hz, 2H), 3.32 (d, J=8.0 Hz, 2), 6.58 (br t,J=5.9 Hz, 1H), 10.73 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ29.57, 29.79,30.79, 172.50, 176.81; LCMS (m/e): 223 (M+H₂O), 206 (M+1).

3b. (N-3{-[3-(piperidylmethyl)phenoxy]propyl}carbamoyl)methyl3-[N-(2-methyl-2 sulfanylpropyl)carbamoyl]propanoate

To an ice-cooled solution of2-hydroxy-N-{3-[3-(piperdylmethyl)phenoxy]propyl}acetamide (1.12 g, 3.66mmol), the product of Example 3a (0.83 g, 4.04 mmol) and DMAP (30 mg) indichoromethane (50 mL) was added a solution of 1 M DCC indichloromethane (4.75 mL, 4.75 mmol). The reaction was stirred at 0° C.for 30 minutes and at room temperature for 2 hours. Additional2-hydroxy-N-{3-[3-(piperdyl-methyl)phenoxy]propyl}acetamide (0.39 g) and1 M DCC in dichloromethane (2 mL) was added and stirring was continuedfor 1 hour. The reaction was washed with water (50 mL) and the aqueousphase was extracted with dichloromethane (2×50 mL). The combined organicphase was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude product was purified by flash chromatography (SiO₂, ethyl acetate,then 10% methanol/ethyl acetate, followed by 1:10:90triethylamine/methanol/ethyl acetate) to afford the title compound as aviscous oil (1.099 g, 60.9%). ¹H NMR (300 Hz, CDCl₃): δ1.31 (s, 6 H),1.33 (s, 1 H), 1.41-1.44 (m, 2 H), 1.53-1.67 (m, 4 H), 2.01-2.07 (m, 2H), 2.37 (m, 4 H), 2.63 (m, 4 H), 3.27 (d, J=6.2 Hz, 2 H), 3.39 (s, 2H), 3.47 (q, J=6.0 Hz, 2 H), 4.01 (t, J=6.1 Hz, 2H), 4.63 (s, 2H), 6.39(br t,J=5.8 Hz, 1 H), 6.76 (dd, J=7.5 and 1.9 Hz, 1 H), 6.87 (s, 1 H),6.89 (d, J=6.6 Hz, 1 H), 7.19 (t, J=7.9 Hz, 1H), 7.50 (br t, 5.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ24.21, 25.81, 28.78, 29.47, 29.82, 30.78,36.59, 45.09, 52.20, 54.35, 62.73, 63.63, 65.54, 112.73, 115.16, 121.53,128.89, 140.14, 158.64, 167.52, 171.69, 171.80; MS (m/e): 494 (M⁺).

3c. (N-3{-[3-(piperidylmethyl)phenoxy]propyl}carbamoyl)methyl3-{N-[2-methyl-2-(nitrosothio)propyl]carbamoyl}propanoate

To a solution of the product of Example 3b (0.486 g, 0.98 mmol) indichloromethane (10 mL) was added a saturated solution of HCl inmethanol (2 mL). Tert-butyl nitrite (0.127 mL, 1.08 mmol) was introducedto the reaction which immediately turned greenish. After 30 minutes, thereaction was evaporated under vacuum. The residue was partitionedbetween aqueous saturated potassium bicarbonate (30 mL) anddichloromethane (30 mL). After separation, the aqueous layer wasextracted with dichloromethane (2×20 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated under vacuum to afford the crudeproduct which was purified by flash chromatography (SiO₂, ethyl acetate,then 10% methanol/ethyl acetate, then 1:10:90triethylamine/methanol/ethyl acetate). The title compound (0.421 g,81.8%) was isolated as a green oil. ¹H NMR (300 MHz, CDCl₃): δ1.34-1.43(m, 2 H), 1.54-1.57 (m, 4 H), 1.82 (s, 6 H), 2.04-2.07 (m, 2 H), 2.36(m, 4 H), 2.61 (m, 4 H), 3.46 (s, 2 H), 3.47 (q, J=5.9 Hz, 2 H), 3.96(d, J=6.5 Hz, 2 H), 4.02 (t, J=6.0 Hz, 2 H), 4.60 (s, 2 H), 6.65 (br t,J=5.6 Hz, 1 H), 6.76 (d, J=7.7 Hz, 1 H), 6.87 (s, 1 H), 6.88 (d, J=6.3Hz, I H), 7.19 (t, J=8.0 Hz, 1 H), 7.52 (br t, J=5.2 Hz, 1 H); ¹³C NMR(75 MHz, CDCl₃): δ24.16, 25.74, 26.62, 28.75, 29.42, 30.65, 36.61,49.32, 54.33, 56.94, 62.66, 63.60, 65.50, 112.76, 115.18, 121.58,128.90, 139.99, 158.63, 167.54, 171.78, 172.12; MS (m/e): 523 (M⁺).

Example 4 Comparative In Vivo Gastric Lesion Activity

The ethanol/HCl mixture-induced gastric lesion test in rats described byTakeuchi et al, J. Pharmacol. Exp. Ther., 286: 115-121 (1998), was usedto evaluate the gastric lesion activity. Male Sprague Dawley rats(Charles River Laboratories, Wilmington, Mass.) weighing 230-250 g wereused for the experiments. The rats were housed with laboratory chow andwater ad libitum prior to the study. The rats were fasted for 24 hourswith free access to water and then dosed by oral gavage with vehicle orwith the test compounds given at a volume of 0.5 ml/100 g body weight.Thirty minutes after oral dosing all the rats received 1 ml of asolution of 60% ethanol in 150 mM HCl intragastrically. Food waswithheld after dosing. Sixty minutes after ethanol/HCl, rats wereeuthanized by pre-charged CO₂. The stomachs were dissected along thegreater curvature, washed with a directed stream of 0.9% saline andpinned open on a sylgard based petri dish for examination of thehemorrhagic lesions. Gastric lesion score was expressed in mm andcalculated by summing the length of each lesion as described byAl-Ghamdi et al, J. Int. Med. Res., 19: 2242 (1991). Results areexpressed as the mean±standard error of the mean. Statistical analysiswere conducted using ANOVA test followed by a Student-Newman-Keulspost-hoc test using the Abacus Concepts, Super Anova computer program(Abacus Concepts, Inc., Berkeley, Calif.).

FIG. 7 compares the gastric lesion activity of vehicle alone, cimetidinein vehicle and Example 1 (nitrosylated cimetidine) in vehicle.Ethanol/HCl mixture produced gastric lesion in the control rats treatedwith vehicle (0.5% Methocel). Cimetidine at doses of 160 and 320 μmol/kgfailed to significantly inhibit the formation of gastric lesions.However, Example 1, the nitrosylated cimetidine derivative, at 160 and320 μmol/kg significantly inhibited the formation of gastric lesionsproduced by the ethanol/HCl mixture.

The disclosure of each patent, patent application and publication citedor described in the present specification is hereby incorporated byreference herein in its entirety.

Although the invention has been set forth in detail, one skilled in theart will appreciate that numerous changes and modifications can be madeto the invention, and that such changes and modifications can be madewithout departing from the spirit and scope of the present invention.

What is claimed is:
 1. A composition comprising at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and at least one S-nitrosothiol.
 2. The composition of claim 1, wherein the at least one H₂ receptor antagonist compound is cimetidine, nizatidine, ranitidine, roxatidine, famotidine, ebrotidine, burimamide, metiamide, tiotidine or oxmetidine.
 3. The composition of claim 1 further comprising a pharmaceutically acceptable carrier.
 4. The composition of claim 1, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.
 5. The composition of claim 1, wherein the S-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(m)SNO; (ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); or (iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein m is an integer from 2 to 20; R_(e) and R_(f) are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a carbamoyl, a urea, a nitro, —T—Q, or (C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f) taken together with the carbon atom to which they are attached are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO₂; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lone pair of electrons, a hydrogen or an alkyl group; R_(i), is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic or inorganic cation; with the proviso that when R_(i), is —CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂—).M⁺; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
 6. A composition comprising at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and at least one compound that induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
 7. A composition comprising at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and at least one compound selected from: (i) a compound that comprises at least one ON—O— or ON—C— group; and (ii) a N-oxo-N-nitrosoamine having the formula: R¹R²N—N(O—M⁺)—NO, wherein R¹ and R² are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M⁺ is an organic or inorganic cation.
 8. The composition of claim 7, wherein the compound comprising at leas one ON—O— group or ON—C— group is an ON—O-polypeptide, an ON—C-polypeptide, an ON—O-amino acid, an ON—C-amino acid, an ON—O-sugar, an ON—C-sugar, an ON—O-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, an ON—O-heterocyclic compound or a ON—C-heterocyclic compound.
 9. The composition of claims 1, 6 or 7, further comprising at least one of a nonsteroidal antiinflammatory drug, an antacid, a bismuth-containing reagent, and an anti-viral agent.
 10. A method for treating or preventing a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claims 1, 6 or
 7. 11. The method of claim 10, further comprising administering to the patient a therapeutically effective amount of an antacid.
 12. The method of claim 10, wherein the gastrointestinal disorder is a peptic ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a stress ulcer, a bleeding peptic ulcer, short bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
 13. A method for improving the gastroprotective properties, the anti-Helicobacter properties, or the antacid properties of an H₂ receptor antagonist comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claims 1, 6 or
 7. 14. The method of claim 13, further comprising administering to the patient a therapeutically effective amount of a bismuth-containing reagent.
 15. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug to a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one nonsteroidal antiinflammatory drug, at least one H₂ receptor antagonist compound, and at least compound selected from an S-nitrosothiol, L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, a compound that comprises at least one ON—C-group, a compound that comprises at least one ON—C— group, and an N-oxo-N-nitrosoamine having the formula: R¹R²N—N(O—M⁺)—NO, wherein R¹ and R² are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M⁺ is an organic or inorganic cation.
 16. A method for preventing or treating a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one H₂ receptor antagonist or a pharmaceutically acceptable salt thereof, and at least one compound selected from an S-nitrosothiol, L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, a compound that comprises at least one ON—O-group, a compound that comprises at least one ON—C— group, and an N-oxo-N-nitrosoamine having the formula: R¹R²N—N(O—M⁺)—NO, wherein R¹ and R² are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M⁺is an organic or inorganic cation.
 17. The method of claim 16, further comprising administering at least one antacid.
 18. The method of claim 16, wherein the gastrointestinal disorder is a peptic ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a stress ulcer, a bleeding peptic ulcer, short bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
 19. A kit comprising at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and at least one compound selected from an S-nitrosothiol, L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, a compound that comprises at least one ON—O-group, a compound that comprises at least one ON—C— group, and an N-oxo-N-nitrosoamine having the formula: R¹R²N—N(O—M⁺)—NO, wherein R¹ and R² are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M⁺ is an organic or inorganic cation.
 20. The kit of claim 19, wherein the H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and the at least one compound selected from an S-nitrosothiol, L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, the compound comprising at least one ON—O— group, the compound comprising at least one ON—C— group, or the N-oxo-N-nitrosoamine are separate components in the kit or are in the form of a composition in the kit.
 21. The kit of claim 19, further comprising a nonsteroidal antiinflammatory drug, an antacid, a bismuth-containing reagent or an anti-viral agent.
 22. The composition of claim 6, wherein the at least one H₂ receptor antagonist compound is cimetidine, nizatidine, ranitidine, roxatidine, famotidine, ebrotidine, burimamide, metiamide, tiotidine or oxmetidine.
 23. The composition of claim 6, further comprising a pharmaceutically acceptable carrier.
 24. The composition of claim 6, wherein the compound that induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine or glutamine.
 25. The composition of claim 7, wherein the at least one H₂ receptor antagonist compound is cimetidine, nizatidine, ranitidine, roxatidine, famotidine, ebrotidine, burimamide, metiamide, tiotidine or oxmetidine.
 26. The composition of claim 7, further comprising a pharmaceutically acceptable carrier.
 27. A composition comprising at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, in combination with at least one compound that comprises at least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group.
 28. The composition of claim 27, wherein the at least one H₂ receptor antagonist compound is cimetidine, nizatidine, ranitidine, roxatidine, famotidine, ebrotidine, burimamide, metiamide, tiotidine or oxmetidine.
 29. The composition of claim 27, further comprising a pharmaceutically acceptable carrier.
 30. The composition of claim 27, wherein the compound comprising at least one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group is an O₂N—O-polypeptide, an O₂N—N-polypeptide, an O₂N—S-polypeptide, an O₂N—C-polypeptide, an O₂N—O-amino acid, O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—C-amino acid, an O₂N—O-sugar, an O₂N—N-sugar, O₂N—S-sugar, an O₂N—C-sugar, an O₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, an O₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—C-hydrocarbon, an O₂N—O-heterocyclic compound, an O₂N—N-heterocyclic compound, an O₂N—S-heterocyclic compound or an O₂N—C-heterocyclic compound.
 31. A method for treating or preventing a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim
 27. 32. The method of claim 31, wherein the gastrointestinal disorder is a peptic ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a stress ulcer, a bleeding peptic ulcer, short bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
 33. A method for improving the gastroprotective properties, the anti-Helicobacter properties, or the antacid properties of an H₂ receptor antagonist compound comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim
 27. 34. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug to a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one composition of claim
 27. 35. A method for improving the gastroprotective properties, the anti-Helicobacter properties or the antacid properties of an H₂ receptor antagonist compound comprising administering to a patient in need thereof a therapeutically effective amount of a bismuth complex comprising at least one composition of claim
 27. 36. The method of claims 31, 33, 34 or 35, wherein the composition is administered orally, bucally, parentally, by inhalation spray, by topical application, by injection or transdermally.
 37. A kit comprising at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and at least one compound that comprises at least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group.
 38. The kit of claim 37, wherein the H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and the compound that comprises at least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group are separate components in the kit or are in the form of a composition in the kit.
 39. A method for preventing or treating a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to a patient in need thereof a therapeutically effective amount of at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, in combination with at least one compound that comprises at least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group.
 40. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug to a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, in combination with at least one compound that comprises at least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group.
 41. The method of claims 39 or 40, wherein the at least one H₂ receptor antagonist compound is cimetidine, nizatidine, ranitidine, roxatidine, famotidine, ebrotidine, burimamide, metiamide, tiotidine or oxmetidine.
 42. The method of claims 39 or 40, further comprising a pharmaceutically acceptable carrier.
 43. The method of claims 39 or 40, wherein compound comprising at least one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group is an O₂N—O-polypeptide, an O₂N—N-polypeptide, an O₂N—S-polypeptide, an O₂N—C-polypeptide, an O₂N—O-amino acid, O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—C-amino acid, an O₂N—O-sugar, an O₂N—N-sugar, O₂N—S-sugar, an O₂N—C-sugar, an O₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, an O₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—C-hydrocarbon, an O₂N—O-heterocyclic compound, an O₂N—N-heterocyclic compound, an O₂N—S-heterocyclic compound or an O₂N—C-heterocyclic compound.
 44. The method of claims 39 or 40, wherein the at least one H₂ receptor antagonist compound or a pharmaceutically acceptable salt thereof, and the at least one compound that comprises at least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group are administered orally, bucally, parentally, by inhalation spray, by topical application, by injection or transdermally.
 45. The method of claim 10, wherein the composition is administered orally, bucally, parentally, by inhalation spray, by topical application, by injection or transdermally.
 46. The method of claim 13, wherein the composition is administered orally, bucally, parentally, by inhalation spray, by topical application, by injection or transdermally.
 47. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug comprising administering to a patient in need thereof a therapeutically effective amount of at least one nonsteroidal antiinflammatory drug and at least one composition of claims 3, 23 or
 26. 48. A method for improving the gastroprotective properties, the anti-Helicobacter properties or the antacid properties of an H₂ receptor antagonist compound comprising administering to a patient in need thereof a therapeutically effective amount of a bismuth complex comprising at least one composition of claims 3, 23 or
 26. 49. The composition of claim 27, further comprising at least one of a nonsteroidal antiinflammatory drug, an antacid, a bismuth-containing reagent, and an anti-viral agent.
 50. The method of claim 31, further comprising administering to the patient a therapeutically effective amount of an antacid.
 51. The method of claim 33, further comprising administering to the patient a therapeutically effective amount of a bismuth-containing reagent.
 52. The method of claim 39, further comprising administering to the patient at least one antacid.
 53. The method of claim 39, wherein the gastrointestinal disorder is a peptic ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a stress ulcer, a bleeding peptic ulcer, short bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
 54. The kit of claim 37, further comprising a nonsteroidal antiinflammatory drug, an antacid, a bismuth-containing reagent or an anti-viral agent.
 55. The composition of claim 1, wherein the compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is an S-nitrosothiol. 